Endometrial cancer (EC) is the most common gynaecological malignancy in the developed world and 4th most common women’s cancer in the UK. Although approximately 75% of women present with surgically resectable disease, 20% of these will relapse and 25% of initial diagnoses occur with metastatic disease. There are currently no validated biomarkers to assess treatment response or target molecular therapies, despite evidence for targetable aberrations in the literature. The PI3K pathway in particular is commonly mutated in EC and stathmin is a recently identified phosphoprotein associated with PI3K pathway activation and with prognostic significance in EC. I investigated biomarker development and novel pathways in EC in two ways: firstly, through a feasibility study of circulating tumour cell (CTC) enumeration and molecular profiling (MP) in patients with advanced endometrioid and non-endometrioid EC (EEC and NEEC); and secondly, through methylation and copy number variation (CNV) studies on formalin-fixed paraffin-embedded (FFPE) and fresh frozen (FF) EEC. CTCs have prognostic and predictive significance in a number of cancers, with increasing evidence on CTC MP. CTC enumeration and assessment of stathmin overexpression was performed on the validated Veridex CellSearch platform and shown to be feasible. In addition, CTC positivity was associated with worse survival and there was a subset of patients for whom a positive CTC count was predictive of outcome on chemotherapy. The second component focused on methylation and CNV analysis in the different phases of endometrial carcinogenesis from normal endometrium to atypical endometrial hyperplasia (AEH) and EEC. By extracting DNA from FFPE and FF EEC and using the Illumina Infinium HumanMethylation450 BeadChip, I was able to demonstrate these methods were feasible and that differential methylation and CNV was evident in the transition from normal endometrium through to AEH and EEC. This research provides a basis for further biomarker development and novel target selection in EC.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:647305 |
| Date | January 2015 |
| Creators | Lemech, C. R. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1464123/ |
Page generated in 0.0021 seconds